Nicotinamide nucleotide transhydrogenase (NNT) acts as a novel modulator of macrophage inflammatory responses

FASEB J. 2012 Aug;26(8):3550-62. doi: 10.1096/fj.11-199935. Epub 2012 May 16.


Nicotinamide nucleotide transhydrogenase (NNT) is a mitochondrial redox-driven proton pump that couples the production of NADPH to the mitochondrial metabolic rate. In this study, we demonstrated for the first time that NNT has a significant effect in the modulation of the immune response and host defense against pathogens. We found that NNT mRNA is enriched in immune system-related tissues and regulated during macrophage activation. Overexpression of NNT in a macrophage cell-line resulted in decreased levels of reactive oxygen species (ROS) and nitric oxide upon induction of the macrophage inflammatory responses. These cells failed to fully activate MAPK signaling pathways, resulting in defective secretion of proinflammatory cytokines in response to LPS, and were inefficient in clearance of intracellular bacteria. We have shown that C57BL/6J mice, which have a deletion in the Nnt gene, exhibited greater resistance to acute pulmonary infection with Streptococcus pneumoniae. Macrophages from these mice generated more ROS and established a stronger inflammatory response to this pathogen. Our results demonstrate a novel role for NNT as a regulator of macrophage-mediated inflammatory responses.

MeSH terms

  • Animals
  • Cell Line
  • Immune System / enzymology
  • Inflammation / physiopathology*
  • Lung / pathology
  • Macrophages / enzymology
  • Macrophages / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • NADP Transhydrogenases / physiology*
  • Phagocytosis / physiology
  • Pneumococcal Infections / pathology
  • Pneumococcal Infections / physiopathology
  • Pneumonia, Bacterial / etiology
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects
  • Tumor Necrosis Factor-alpha / pharmacology


  • Reactive Oxygen Species
  • Tumor Necrosis Factor-alpha
  • NADP Transhydrogenases